Presentation on theme: "Reactions of alkyl halides: nucleophilic Substitution and elimination"— Presentation transcript:
1 Reactions of alkyl halides: nucleophilic Substitution and elimination Dr. SheppardCHEM 2412Fall 2014McMurry (8th ed.) sections 10.1, , ,11.12
2 Alkyl Halides Contain F, Cl, Br, or I Widely used in: Structure: Synthesis (electrophilic carbon and easy functional group transitions)Solvents (CCl4, CHCl3, CH2Cl2)Industrial applicationsStructure:
3 Properties of Alkyl Halides Bond strengthMeasured by bond dissociation energyInversely proportional to bond lengthElectronegativity and small size of F keep bonding electrons closeC-F > C-Cl > C-Br > C-Ishort longstrong weakWhich C-X bond is easier to break, C-Cl or C-Br?
4 Properties of Alkyl Halides PolarityAlkyl halides have substantial dipole momentsDipole moments depend on:Electronegativity of XF > Cl > Br > IC-X bond lengthC-I > C-Br > C-Cl > C-FPolarizability of electrons (ease of distribution of electron density)I > Br > Cl > FSince these trends oppose one another, the trend in molecular dipole moment is not periodicC-Cl > C-F > C-Br > C-I
6 Reactions of Alkyl Halides Carbon bonded to X is electron-poor (electrophilic)Will react with nucleophilesNucleophiles are also bases! So, there are two competing reactions:SubstitutionNucleophile substitutes for X (the leaving group)EliminationNucleophile/base removes H, eliminates HX to yield an alkene
7 Substitution vs. Elimination How do we know which reaction will occur?In this chapter:Mechanisms of substitutionMechanisms of eliminationSubstitution vs. elimination
8 I. Nucleophilic Substitution Nucleophile substitute for leaving group (X)Example:CH3CH2CH2Br + NaOCH3 → CH3CH2CH2OCH3 + NaBrLeaving group =Nucleophile =
9 StereochemistryWhen the product has a stereocenter, we must consider stereochemistryExamples:How can we explain the observed stereochemistry?There is more than one possible mechanismSN2 and SN1 (differ in timing of C-X breaking and C-Nu formation)
10 The SN2 Reaction Bimolecular nucleophilic substitution Bimolecular = two species (RX and Nu) participate in RDSRate = k [RX] [Nu]Mechanism:Single stepNo intermediatesBonds broken and made simultaneously (concerted)Same mechanism as acetylide ion and methyl/primary RX
13 SN2 Energy DiagramOne stepExothermicEReaction Coordinate
14 SN2 StereochemistryNucleophile attacks reaction center (electrophilic carbon) from the direction opposite the leaving groupBackside attackCauses change in configurationStereocenter: S ↔ RRings: cis ↔ transEx: (S)-2-bromobutane + NaOH
15 SN2 Characteristics Factors influencing the rate of SN2 reaction: Alkyl halide structureNucleophileLeaving groupSolvent
16 SN2 Characteristics: RX Structure Steric effectsNucleophile must have access to reaction centerAccess is hindered with bulky substituents
17 SN2 Characteristics: RX Structure Trends in RX reactivity:Methyl halide most reactiveTertiary alkyl halide not likely to reactBranched 1° and 2° alkyl halides react slower than unbranchedVinyl and aryl halides will not react
18 SN2 Characteristics: Nucleophile Nucleophile: contains lone pairSome nucleophile are better than othersBetter nucleophile = faster SN2 reactionSome common nucleophiles:What trends do you notice relating nucleophilicity and structure?PoorGoodStrongROHRCO2HH2OFRCO2RSHNH3/NR3ClBrIHSHOROCN
19 Trends in Nucleophile Structure Anions are stronger nucleophiles than neutral moleculesHO > H2ORO > ROH
20 Trends in Nucleophile Structure Less stable anions are stronger nucleophiles than more stable anionsRO > RCO2Generally, nucleophilicity increases down a groupI > Br , Cl > FBulky anions are more likely to act as a base, rather than a nucleophile(CH3)3CO vs. CH3Obase nucleophile
21 Nucleophile Structure Some common good nucleophiles are also strong basesHO-RO-H2N-Some common good nucleophiles are weak basesI--CNRCO2-This will be important later when comparing substitution and elimination
22 SN2 Characteristics: Leaving Group Better LG = faster reactionBetter LG = more stable anion
23 SN2 Characteristics: Solvent Dissolves reactants, creates environment of reaction, can affect outcome of reactionSolvents are either protic or aproticPolar proticH-bond donorContain NH or OHAlcohols, carboxylic acids, amines, waterPolar aproticCannot donate H-bondDimethyl sulfoxide (DMSO)AcetoneAcetonitrileN,N-Dimethylformamide (DMF)
24 SN2 Characteristics: Solvent Polar aprotic solvents solvate cations, but not anionsAnions shielded from d+ by methyl groupsLess solvatedMore available to react as nucleophilesGood for SN2!
25 SN2 Characteristics: Solvent Polar protic solvents solvate both cations AND anionsAnion is well-solvatedLess available to react as nucleophilesNot good for SN2!
26 SN2 Summary Rates of Reaction (Kinetics): What is the rate-determining step for the SN2 reaction?Does the rate of reaction depend on the concentration of alkyl halide only OR both the alkyl halide and nucleophile?Stereochemistry:What happens to a stereocenter (chirality center) during the course of this reaction?Structure of the Alkyl Halide:List alkyl halide type (1, 2, 3) in order of decreasing ability to undergo this type of substitution reaction. Are there any types of alkyl halides that do not undergo this type of reaction? Why?Given this order or reactivity, are electronic factors important for this reaction? Why or why not?Are steric factors important for this reaction? Why or why not?The Nucleophile:Is the nature of the nucleophile important for the SN2 reaction? Why or why not?The Leaving Group:Rank the leaving groups of alkyl halides (F-, Cl-, Br-, I-) in their ability to “leave.” Why is this trend observed?The Solvent:How do polar aprotic solvents and polar protic solvents affect substitution reactions?What are the best solvents for the SN2 reaction? Why?
27 The SN1 Reaction Unimolecular nucleophilic substitution Unimolecular = one species (RX) participates in RDSRate = k [RX]Mechanism:Multiple stepsCarbocation intermediateC-X bon broken before C-Nu bond formedWhich step is RDS?
35 SN1 Characteristics: RX Structure Trends in RX reactivity:Tertiary alkyl halides most reactivePrimary alkyl halides will not form unless allylic or benzylic
36 SN1 Characteristics: Nucleophile Nucleophile is not important for SN1 reactionsNot in the rate equationEven poor nucleophiles are OK for SN1H2O, ROH, etc.
37 SN1 Characteristics: Leaving Group Better LG = faster reaction
38 SN1 Characteristics: Leaving Group SN1 on alcoholsNeed strong acid to protonate –OH and form a better LG
39 SN1 Characteristics: Solvent Polar protic solvents = faster reactionSolvate both cations AND anionsSpeed up RDS by solvating and separating carbocation intermediate and leaving group anionGood for SN1!Commonly SN1 nucleophile = solventSolvolysis reaction
40 SN1 Summary Rates of Reaction (Kinetics): What is the rate-determining step for the SN1 reaction?Does the rate of reaction depend on the concentration of alkyl halide only OR both the alkyl halide and nucleophile?Stereochemistry:What happens to a stereocenter (chirality center) during the course of this reaction?Structure of the Alkyl Halide:List alkyl halide type (1, 2, 3) in order of decreasing ability to undergo this type of substitution reaction. Are there any types of alkyl halides that do not undergo this type of reaction? Why?Given this order or reactivity, are electronic factors important for this reaction? Why or why not?Are steric factors important for this reaction? Why or why not?The Nucleophile:Is the nature of the nucleophile important for the SN1 reaction? Why or why not?The Leaving Group:Rank the leaving groups of alkyl halides (F-, Cl-, Br-, I-) in their ability to “leave.” Why is this trend observed?The Solvent:How do polar aprotic solvents and polar protic solvents affect substitution reactions?What are the best solvents for the SN1 reaction? Why?
41 Rearrangements possible Summary of SN2 vs. SN1SN2SN1Driving forceSteric factorsElectronic factorsAlkyl halideMethyl1°2°AllylicBenzylic3°Stereochemistry100% inversionRacemic mixtureRegiochemistryNo rearrangementsRearrangements possibleNucleophileGoodGood or poorSolventAproticProtic
42 Predict the substitution mechanism and products for the following reactions…
43 Carbocation Rearrangements Carbocation intermediates can rearrange to form a more stable carbocation structureTypes of rearrangements:Hydride shiftAlkyl shift (methyl or phenyl)Can SN2 reactions undergo rearrangement?
48 Elimination Regiochemistry Multiple products can be formed if there is more than one adjacent HHow do we know the major product?
49 Zaitsev’s RuleIn the elimination of HX from an alkyl halide, the more highly substituted alkene product predominatesThis alkene is more stableThere are some exceptions, but this rule is generally trueExample:Which product is major?
50 The E2 Reaction Bimolecular elimination Rate = k [RX] [Base] Mechanism:Single stepConcertedNo intermediatesNeeds a strong base (NaOH, NaOR, NaNH2)
51 E2 Stereochemistry The alkyl halide must have anti-periplanar geometry Anti = H and X on opposite sides of moleculeLess steric strain between base and leaving groupPeriplanar = all 4 reacting atoms (H, C, C, X) are in the same planeMaximizes molecular orbital overlap in transition state
52 What is the major product of E2 reaction of (2S,3R)-2-bromo-3-methylpentane
53 E2 Regiochemistry Usually Zaitsev Formation of non-Zaitsev product: When the base is a bulky baset-BuO- is sterically hindered, does not remove more crowded H
54 E2 Regiochemistry Formation of non-Zaitsev product: When anti-periplanar geometry cannot be achieved (substituted cyclohexanes)Anti-periplanar = trans diaxial
57 The E1 Reaction Unimolecular elimination Rate = k [RX] Mechanism: Multiple stepsCarbocation intermediateWeak base is OK due to reactive R+ intermediateStereochemistry of RX not a factor due to R+ planarityRegiochemistry is Zaitsev
59 E1 Reaction of AlcoholsDehydration of an alcohol to form an alkene is also E1 mechanismReaction is reversibleRemove alkene as formed (distillation) to push to the rightAcid catalyst is neededH3PO4 or H2SO4Protonates –OH to make a better leaving group (H2O)Example:
60 Zaitsev, unless bulky base or no anti-periplanar conformation Summary of E2 vs. E1E2E1Alkyl halide1°2°3°BaseStrongWeakStereochemistryAnti-periplanarn/aRegiochemistryZaitsev, unless bulky base or no anti-periplanar conformationZaitsev
61 Predict the elimination mechanism and products for the following reactions…
62 Outline In this chapter: Mechanisms of substitution SN2SN1Mechanisms of eliminationE2E1Substitution vs. eliminationSN2 or SN1 or E2 or E1
63 III. Substitution vs. Elimination Given starting material and reagentsPredict mechanism and draw productsRemember regiochemistry and stereochemistryWhere do we start?First, look at possible mechanisms for each RX structureThen, compare reaction conditions for each mechanism
64 Possible MechanismsRX StructureSN2SN1E2E1Methyl1°2°3°
65 Reaction Conditions SN2 vs. SN1 E2 vs. E1 SN2 vs. E2 SN1 vs. E1 Good nucleophile and aprotic solvent favor SN2Poor nucleophile and protic solvent favor SN1E2 vs. E1Strong base favors E2Weak base favors E1SN2 vs. E2Good nucleophiles/weak bases favor SN2Good nucleophiles/strong bases and 1° RX result in SN2 and E2Good nucleophiles/strong bases and 2° RX result in E2Bulky bases or branched RX favor E2SN1 vs. E1SN1 and E1 are both favored with weak nucleophiles/basesMixture of products from both SN1 vs. E1 will result anytime a unimolecular mechanism is predicted
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